This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Back ground: Cryptosporidium infection leads to life threatening diarrhea in AIDS patients. Pathogenesis of cryptosporidiosis is due to intestinal physiological alterations. We devised an ex-vivo model using ex-vivo C. parvum infection of jejunal tissues derived from SIV infected macaques and studied the role of substance P (SP) in the pathogenesis of cryptosporidiosis. Methods: We measured jejunal SP mRNA and protein levels using ELISA , and electrophysiological alterations using the Ussing chamber technique in an ex-vivo model of Cryptosporidium infection. Paraformaldehyde fixed jejunum from SIV infected macaques with and without naturally-occurring cryptosporidiosis was studied for SP expression by immunohistochemistry and fluorescence deconvolution microscopy. Results: Ex-vivo Cryptosporidium infected tissues and tissues from SIV infected macaques with naturally-occurring cryptosporidiosis demonstrated elevated SP protein levels compared to tissues from SIV-infected animals without ex-vivo C. parvum infection or tissues from SIV-infected animals that have no evidence of cryptosporidiosis. In our ex-vivo model of Cryptosporidium infection, we demonstrated pathophysiological alterations that were blocked by SP-receptor antagonist treatment. Conclusions: These studies suggest that SP-receptor antagonists could prove useful for treatment of AIDS related cryptosporidiosis.